Abstract

Targeting epigenetic pathways to induce tumor suppressor gene reactivation is a promising approach for cancer therapy. Epigenetic drugs produce impressive responses in some patients; however, treatment options are limited to a small number of drugs. We screened drug libraries for epigenetic activity using a live cell-based assay. We found that around 1% of US-FDA approved drugs have significant epigenetic activity detected by GFP reactivation of a DNA methylated and silenced promoter in colon cancer cells. Newly identified drugs, most prominently cardiac glycosides, induced tumor suppressor gene reactivation and showed selective anticancer apoptosis induction. These drugs did not change DNA methylation or histone acetylation globally but induced gene reactivation and cancer cell killing through calcium signaling leading to nuclear exclusion of chromatin repressors. Our data identify new epigenetic drugs that can be rapidly repurposed for cancer clinical trials and raise questions about the safety of commonly used medications.